Shruthi Ganapuram
Background of Alzheimer’s Pathology
Alzheimer’s disease is defined as a progressive neurodegenerative disease, primarily characterized by cognitive decline and memory loss. The causes of the disease include genetic, environmental, and lifestyle factors. Pathological changes take place in the hippocampus, within the entorhinal cortex, essential to the formation of memories. The discovery of biomarkers for the disease facilitates earlier detection of Alzheimer’s, allowing for better treatment and potential participation in clinical trials.
The exponential progression of Alzheimer’s results in the death of basal forebrain cholinergic neurons— including amyloid plaques that build up between nerve cells– due to deposits of abnormal proteins that define specific histological markers. Therefore, these markers are crucial for the diagnosis in order to differentiate from other clinical neurodevelopmental disorders with which consist of a distinct pathology.
In order to understand the histological characteristics associated with the amyloid plaques, biomarkers are critical for early detection and diagnosis, evaluation of disease mechanisms, and monitoring of overall disease progression.
Histological Markers in Alzheimer’s Disease
The specificity of these markers allows for a comprehensive study of the pathological differences that inherently differentiate Alzheimer’s from other neurological disorders. These histological markers include the development of abnormal amyloid and tau tangle protein proliferation within the living brain. Further aggregation of the hyperphosphorylated tau protein into “tangles” can disrupt the functionality of the microtubules in neurons, which can affect synaptic plasticity and neuronal firing stability. These proteins can become damaged over time and can detach from their axons, allowing for the tau proteins to cluster and form neurofibrillary tangles, ultimately leading to neuronal death.
Types of Biomarkers and Disease Mechanisms
The majority of Alzheimer’s biomarkers can be categorized as cognitive, pathophysiological, and topographic markers for clinicians to differentiate and diagnose the phenotypic qualities of Alzheimer’s. Pathophysiologic biomarkers include amyloid positron emission tomography(PET), cerebrospinal fluid(CSF) through imaging technologies, and high concentrations of amyloid, tau, and other plasma protein biomarkers. A distinct blood-based biomarker of Alzheimer’s is the Aβ42/40, which reveals an increased deposition of amyloid-beta plaques in the brain, a hallmark characteristic of Alzheimer’s disease.
In a study published investigating the effect of intensive lifestyle changes on the progression of mild cognitive impairment due to Alzheimer’s disease, this Aβ42/40 ratio was used to examine the association of this blood-based biomarker on the diagnosis of Alzheimer’s which proved to strongly support a significance for the blood-based biomarkers in early dementia due to Alzheimer’s.
In addition to strongly supporting the diagnosis of Alzheimer’s, biomarkers monitor the progression of the disease over a period of time. For instance, longitudinal studies for patients with mild-cognitive impairment(MCI) use tau PET and structural MRI imaging to examine cognitive decline by measuring the proliferation of abnormal neurofibrillary tangles on neuronal firing. To corroborate the imaging data collected to examine tau protein buildup, cognitive biomarkers can be used in tandem with plasma biomarkers to monitor the disease progression through cognitive and functional tests. Tests such as the Clinical Dementia Rating-Sum of Boxes(CDR-SB) and the Alzheimer’s Disease Assessment Scale(ADAS-Cog) are factored into measuring the extent of cognitive decline. Furthermore, these tests enable clinicians to rapidly initiate therapies.
Future Research/Implications
Biomarkers play an important role in clinical decision making, particularly in aiding early diagnosis and identifying patients at risk. Future research to make biomarkers less invasive will increase access to screening for and monitoring of Alzheimer’s. With the primary focus on diagnosing Alzheimer’s at its earliest stage, biomarkers quantify the amyloid-beta, tau, and other proteins, expediting identification of Alzheimer’s for clinical treatment plans.
By enhancing diagnostic accuracy, multimodal lifestyle recommendations can be made to proactively treat Alzheimer’s and be used to enhance clinical accuracy in research.
References
Alzheimer’s Disease fact Sheet. (2023, April 5). National Institute on Aging. https://www.nia.nih.gov/health/alzheimers-and-dementia/alzheimers-disease-fact-sheet
Dubois, B., Von Arnim, C. a. F., Burnie, N., Bozeat, S., & Cummings, J. (2023). Biomarkers in Alzheimer’s disease: role in early and differential diagnosis and recognition of atypical variants. Alzheimer’s Research & Therapy, 15(1). https://doi.org/10.1186/s13195-023-01314-6
Ornish, D., Madison, C., Kivipelto, M., Kemp, C., McCulloch, C. E., Galasko, D., Artz, J., Rentz, D., Lin, J., Norman, K., Ornish, A., Tranter, S., DeLamarter, N., Wingers, N., Richling, C., Kaddurah-Daouk, R., Knight, R., McDonald, D., Patel, L., . . . Arnold, S. E. (2024). Effects of intensive lifestyle changes on the progression of mild cognitive impairment or early dementia due to Alzheimer’s disease: a randomized, controlled clinical trial. Alzheimer S Research & Therapy, 16(1).
Wang, J., Xia, Y., Grundke-Iqbal, I., & Iqbal, K. (2012). Abnormal hyperphosphorylation of TAU: sites, regulation, and molecular mechanism of neurofibrillary degeneration. Journal of Alzheimer’s Disease, 33(s1), S123–S139. https://doi.org/10.3233/jad-2012-129031
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